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FDA:根据临床相关性建立杂质接受标准作为NDAs、ANDAs和BLAs规范的一部分
2018-03-16 09:38:15 作者: 来源:药事纵横 文字大小:[][][]
FDA于2018年01月18日发布了Establishing Impurity Acceptance Criteria As Part of Specifications for NDAs, ANDAs, and BLAs Based on Clinical Relevance指导原则,药事纵横翻译团队对其进行了翻译,分享给大家。



Purpose目的

This MAPP provides guiding principles and approaches for establishing drug substance and drug product impurity1 acceptance criteria for non-mutagenic impurities in new drug applications(NDAs), abbreviated new drug applications (ANDAs), and biologics license applications (BLAs), based on the consideration of clinical relevance.2

该MAPP基于临床相关性的考虑[2]为建立新药申请(NDAs)、简化新药申请(ANDAs)和生物制剂许可申请(BLAs)的原料药和制剂中非致突变杂质的接受标准提供了指导原则和方法[1]。

While ICHQ3A(R2) and Q3B(R2)3 apply to new molecular entities produced by chemical synthesis, the principles of these guidances and the principles of this MAPP may apply to other drug substances and drug products, including some semi-synthetic and fermentation products, and synthetic peptides4,submitted in NDAs and ANDAs.

虽然ICH Q3A(R2)和Q3B(R2)[3]适用于化学合成的新型分子实体,但这些指导原则和MAPP中的原则可能也适用于其他原料药和制剂,包括在NDA和ANDA中递交的一些半合成产品、发酵产品及合成多肽类[4]。

The principles in this MAPP may also be used to establish acceptance criteria for DNA-reactive (i.e., mutagenic) impurities that are generally controlled at tighter limits according to the ICH M75.

根据ICH M7[5]对于DNA活性(即致突变性)的杂质一般控制更严格的限度,该MAPP的原则也适用于建立这类杂质的接受标准。

The principles in this MAPP may also apply to investigational drug substances and drug products, depending on the risk.

根据风险,该MAPP中的原则也可能适用于临床实验的原料药和制剂。

Where the active ingredient is a single enantiomer, the principles in this MAPP may alsoapply to associated enantiomeric impurities.

当活性成分是单一对映异构体时,该MAPP中的原则也可适用于相关的对映体杂质。

Please note that the principles that guide the development of a specification can be impacted by the assessment of risk to safety and efficacy based on context of use as well as other factors, such as clinical experience. The context of use includes, but is not limited to, dosage forms, dosing regimens, route and duration of drug administration, clinical indications, and the intended patient populations (e.g., pediatric or geriatric populations). Therefore, an impurity acceptance criterion cannot be established by one definitive approach and instead needs to be established on a case-by-case basis.

值得注意的是,基于使用环境及其他因素(如临床经验),指导制定规范的原则可能受安全性和疗效风险评估的影响。使用环境包括但不限于剂型、给药方案、给药途径和持续时间、临床适应症和预期的患者群体(例如儿科或老年人群)。

因此,不能通过一种明确的方法代替需要根据具体情况来确定杂质接受标准。

The following are excluded from this MAPP:

以下内容不包括在MAPP中:

s Residual solvents and elemental impurities, as these are adequately addressed in ICH Q3C and ICH Q3D. Refer to ICH Q3C and ICH Q3D for establishing limits for these impurities.

残留溶剂和元素杂质,这些在ICH Q3C和ICH Q3D中进行了充分的说明。参见ICHQ3C和ICH Q3D建立这些杂质的限度。

s Extraneous contaminants that should not occur in drug substances and drug products, and are appropriately addressed by Good Manufacturing Practices(e.g., adventitious viral, bacterial, and mycoplasma contamination).

原料药和制剂中不应含有的外来污染物,并通过良好生产规范<GMP>(例如,不定的病毒,细菌和支原体污染)适当解决。

s Microbiological attributes (e.g., endotoxin, microbial limits).

微生物属性(如内毒素,微生物限度)。

s Leachables from the container closure system6.

来自容器封闭系统的可溶物[6]。

s Polymorphic forms7.

多态形式[7]。



Background 背景

To provide assurance that a product performs as is intended, there is a need to establish impurity acceptance criteria. Currently, the establishment of a drug substance and drug product impurity acceptance criterion can be supported by clinical data, nonclinical data (e.g., in silico, in vitro, and animal data),comparative impurity analysis of the proposed drug product with an FDA approved drug product (listed drug or reference listed drug (RLD)), analytical precision of the method used to measure the impurity, and manufacturing process capability. The intent of this MAPP is to clarify the types of data and information needed as well as the limitations when establishing impurity acceptance criteria. In general, the types of data and information should be guided by the consideration of clinical impact of impurity levels, as opposed to manufacturing process capability, to ensure the acceptance criteria are clinically relevant.

为保证产品按预期进行,需要建立杂质接受标准。目前,临床数据、非临床数据(例如,计算机,体外和动物数据)、与FDA批准药物(上市药物或参比制剂)进行杂质分析比较,测定杂质方法的精密度和生产过程控制都可以支持原料药和制剂中杂质接受标准的制定。这个MAPP的目的是阐明所需的数据、信息的类型以及建立杂质接受标准的局限性。一般来说,数据和信息的类型应由临床杂质水平的影响决定,与生产过程控制不同,以确保接受标准具有临床相关性。



Policy 政策



The terminology described in ICH Q3A(R2), Q3B(R2), and Q6A shouldgenerally be applied to NDA and ANDA products. Specifically, a specification should include the following, where “specified impurity” is any impurity present at greater than the identification threshold:
ICH Q3A(R2)、Q3B(R2)和Q6A中描述的术语一般应适用于NDA和ANDA产品。具体而言,规范应包括以下内容,其中“特定杂质”是指任何超过鉴定阈值的杂质。




Drug Substance 原料药

s   Each specified identified impurity

每个鉴定的特定杂质

s   Each specified unidentified impurity

每个未鉴定的特定杂质

s   Any unspecified impurity with an acceptance criterion of not morethan (≤) the identification threshold

任何未确定杂质的接受标准不大于鉴定阈值

s   Total impurities

总杂质



Drug Product 制剂

s   Each specified identified degradation product

每个鉴定的降解产物

s   Each specified unidentified degradation product
每个未鉴定的特定降解产物

s   Any unspecified degradation product with an acceptance criterion ofnot more than (≤) the identification threshold

任何未确定的降解产物的接受标准不大于鉴定阈值

s   Total degradation products

总降解产物



2. For products submitted in NDAs and ANDAs where the applicant’s proposed acceptance criteria are not more than the ICH Q3A(R2) or Q3B(R2) qualification threshold, an acceptable limit for a specified impurity in the drug substance and drug product can be proposed and established at the qualification threshold, provided there are no toxicological, immunological, orclinical concerns at this level. For impurities known to be unusually potent, toxic, or have immunological, pharmacological, or clinical concerns, the proposed acceptance criteria based solely on ICH Q3A(R2) and Q3B(R2) qualification threshold are not sufficient and need to be adequately justified.

在NDA和ANDA递交的产品中,申请人提出了接受标准不超过ICH Q3A(R2)或Q3B(R2)界定阈值,对于原料药和制剂中特定杂质的接受限度可以建立界定阈值,并提供在这个水平没有毒性,免疫或临床相关问题。对于已知杂质异常特性,有毒或具有免疫学,药理学或临床问题的杂质,推荐的接受标准仅仅基于ICH Q3A(R2)和Q3B(R2)的界定阈值是不够的,需要有充分的理由。



2.1  The acceptance criterion for total impurities excluding significant human metabolites8, generally, should not exceed the summation of acceptance criteria forindividual specified (identified and unidentified) impurities. Acceptance criterion for individual impurities that are also significant human metabolites should be considered separately. The sum total of all impurity limits,including those for significant metabolites, should not exceed thresholds thatmay compromise product potency/assay through product expiry.

除人体重要代谢物的总杂质的接受标准[8],一般不应超过单个特定杂质(已鉴定和未鉴定)杂质接受标准的总和。人体重要的代谢物的单个杂质的接受标准也应单独考虑。包括重要代谢物在内的所有杂质限度的总和不得超过在整个有效期内可能影响产品效能/含量的阈值。

  

3.      The proposed acceptance criteria should be justified for thefollowing:对于下面拟定的接受标准应说明是合理的:



Products submitted in NDAs and ANDAs where the applicant’s proposed acceptance criteria are greater than ICH Q3A(R2) or Q3B(R2) qualification threshold.

在NDA和ANDA递交的产品中,申请人提出的接受标准大于ICH Q3A(R2)或Q3B(R2)的界定阈值。

(b) Products submitted in NDAs and ANDAs that are excluded from ICHQ3A(R2) and Q3B(R2)9.

在NDA和ANDA中递交的产品不适用于ICAQ3A(R2)和Q3B(R2)[9]。

(c) Products submitted in BLAs9.

在BLAs中递交的产品[9]。



For impurities listed in a specification, the acceptance criteria should be informed by data derived from clinical trials, nonclinical studies(e.g., in silico modeling, in vitro, and animal studies), context of use, prior knowledge, publicly available information10,and analytical capability, as appropriate.



对于标准中列出的杂质,接受标准应通过临床试验,非临床研究(如计算机模拟,体外和动物研究),使用环境,先进的知识,公开信息[10]和分析能力而得到。



4. For some products, such as certain biotechnology and complex products, there may be impurities for which the relationship to stability, potency, or potential adverse clinical effects is not clear. This may be either because the analytical techniques available have not allowed thorough characterization of the impurity, or because data regarding the impact of the impurity on clinical performance are lacking. For instance:



对于一些产品,如某些生物技术和复杂产品,可能存在与稳定性,效能或潜在的不良临床效应关系不明确的杂质。这可能是因为现有的分析技术没有对杂质进行彻底的表征,或者是因为缺乏关于杂质对临床现象影响的数据。例如:

s   There may be a high level of uncertainty regarding the clinical impact of an impurity, such as a peptide- orprotein-related impurity.

可能存在较高水平不确定关于影响临床的影响,如多肽或蛋白质类。



s   An impurity could be a surrogate for other impurities that might be clinically relevant or for which there is increased uncertainty. For example, for toxin-conjugated drug products, asurrogate may be free protein, fragmented protein, or free toxin, and used to represent the appearance or clearance of other dissociated parts of thetoxin-conjugated product.

一个杂质可能是其他可能与临床有关杂质的替代物,或者增加不确定性。例如,对于毒素结合的产品,替代物可以是游离蛋白质,片段化蛋白质或游离毒素,并且用来表示毒素结合产物的其他游离部分的外观或清除。



In these scenarios, the control strategy, including impurity acceptance criteria, should include greater consideration for manufacturing process capability.

在这些情况中,包括杂质接受标准在内的控制策略应更多考虑包括对生产过程控制能力。



5.  While establishment of impurity acceptance criteria should be guided by the totality of the data and consideration of the clinical impact of impurity levels instead of basing the impurity limits solely on the manufacturing process capability, the manufacturing process consistency shouldbe monitored during the production of the drug substance and the drug productas part of the quality system.

尽管建立杂质接受标准应以全部数据为指导,考虑杂质水平的临床影响代替杂质限度仅仅依据在生产过程控制能力,在原料药和制剂生产过程中应监控生产过程的一致性,并作为质量体系的一部分。



6. Office of Biotechnology Products (OBP) immunogenicity reviewers willuse the existing review process and the principles outlined in the FDA guidance for industry Immunogenicity Assessment for Therapeutic Protein Products toassess the immunogenicity risk of a given impurity for implementing this MAPP.

生物技术产品办公室(OBP)免疫原性评审员将使用现有的评审程序和FDA指导原则对工业用治疗性蛋白质产品进行免疫原性评估,以评估实施该MAPP的特定杂质的免疫原性风险。



7.  Other review disciplines (e.g., pharmacology/toxicology (pharm/tox)and clinical) will use existing review processes for implementing this MAPP.
其他学科的审查(例如,药理学/毒理学(药学/毒理学)和临床)将使用现有的审查流程来执行这个MAPP。



Responsibilities 责任



Responsibilities of the review teams in OPQ: Product quality reviewers will discuss or consult with pharm/tox and/or computational toxicology, clinical, and clinical pharmacology review disciplines, asappropriate, when assessing the potential risk of a given impurity or impurities. Assessments or consults should be initiated as early as possible to allow sufficient time for adequate review. Product quality reviewers should identify relevant information in an application before requesting a consult.

OPQ审核小组的责任:在评估给定杂质或杂质的潜在风险时,产品质量评审员将会讨论或咨询毒理学和/或计算毒理学,临床和临床药理学评审员。应尽早启动评估或咨询,以便有足够的时间进行充分的评估。产品质量评审员在请求咨询之前应该在申请书中了解相关信息。



Procedures

1. NDAs and ANDAs: Acceptance Criterion Not More Than the Qualification Threshold

NDAs和ANDAs:接受标准不大于界定阈值

1.1    a specified impurity with a proposed acceptance criterion not more than the qualification threshold, absent other information to support the need for a lower limit, a proposed acceptance criterion up to the ICH Q3A(R2) orQ3B(R2) qualification threshold is generally acceptable.

对于特定杂质拟定的接受标准不大于界定阈值,缺少其他信息来支持更低的限度,则一般达到ICH Q3A(R2)或Q3B(R2)界定阈值的标准是可以接受的。

1.2 Product quality reviewers should perform due diligence in evaluating impurities and the applicability of ICH threshold levels. This evaluation maybe based on a review of the applicant’s submitted safety rationale, previous FDA experience with identical impurities within CDER-regulated products considering the context of use, or information identified from the published literature. Establishing impurities acceptance criteria at the ICH Q3A(R2) andQ3B(R2) qualification thresholds may not apply if any the following are true:

产品质量评审员应该在评估杂质和ICH阈值水平的适用性方面进行尽职调查。此评估可基于对申请人提交的安全原理的审查,以前的FDA考虑到使用环境的CDER管制产品中的相同杂质的经验,或从公开文献中得到鉴定的信息。如果以下情况属实,依据ICH Q3A(R2)和Q3B(R2)认证阈值内建立杂质接受标准可能不适用。

1.2.1       There are known safety data for the impurities based on their structural class (e.g., impurities known to be DNA reactive (i.e., mutagenic) or the presence of a structural alert formutagenicity).

基于已知其结构类别的杂质的安全性数据(例如,已知为DNA活性<即致突变性>)或存在致突变性的结构警报的杂质)。

1.2.2       There is information suggesting that impurities of this class have unusually potent toxicities.

有资料显示这类杂质具有非常强的毒性。

1.2.3       There are compendial limits related to safety which are lower than the ICH qualification thresholds for theimpurities11.

有药典规定与安全性相关的低于ICH界定的杂质限度 [11]。

1.2.4       There are any immunological orother clinical concerns (e.g., pharmacokinetics/pharmacodynamics (PK/PD) activity, target population). 

有任何免疫学或其他临床问题(例如,药代动力学药效学(PK/PD)活性,目标人群)

1.3    If the above information suggests a concern with the proposed impurity level, then assessments or consults should be initiated early during the review cycle to allow sufficient time for adequate review:

如果上述信息表明对所提议的杂质水平有所顾虑,则应早期启动评估或咨询,以便有足够的时间进行充分的评估:

1.3.1       For toxicology relatedconcerns, the product quality reviewer should request a pharm/tox evaluation toassess the risk to patients for impurities at a specified level.

对于毒理学相关的问题,产品质量评审员应要求进行药物毒理评估,以评估患者在特定水平的杂质风险。

1.3.2       For immunological or otherclinical concerns, the appropriate immunogenicity, clinical, and clinical pharmacology reviewers should be involved to assess the risk/benefit topatients. A consult should be issued if they are not already part of the assigned review team.

对于免疫学或其他临床问题,应参与适当的免疫原性,临床和临床药理学评估,以评估患者的风险/益处。如果他们不是已经分配的审查小组的成员,则应该提出咨询意见。



2. NDAs and ANDAs: Acceptance Criterion Greater Than the QualificationThreshold

NDAs和ANDAs:接受标准大于界定阈值

2.1    For a specified impurity with a proposed acceptance criterion greater than the qualification threshold, data from clinical trials,nonclinical (i.e., in silico, in vitro, and animal) studies, prior knowledge,and publicly available information, including those on significant human metabolites provided by the applicant, should be used by the review disciplines, as appropriate, to assess the adequacy of the proposed acceptance criterion. Assessments or consults should be initiated early during the review cycle to allow sufficient time for adequate review. In general, the product quality reviewer should consult with the appropriate pharm/tox, clinical,and/or clinical pharmacology reviewers to conduct the following assessments insupport of the proposed impurity level:

对于大于界定阈值的拟定接受标准的特定杂质,数据来源于临床试验,非临床(即计算机模拟,体外和动物)的研究,优先知识和公开获得的信息(包括所提供的人类重要代谢物的信息)的数据申请人应酌情使用评审专业来评估拟议验收标准是否适当。评估或咨询应在评估的早期进行,以便有足够的时间进行充分的评估。一般来说,产品质量评审员应咨询相应的药物临床,毒理学和/或临床药理学评审员进行以下评估,以支持所提出的杂质水平。

2.1.1       A pharm/tox assessment orconsult for toxicology-related concerns to verify that impurities have been adequately evaluated and the levels of impurities are considered qualified innonclinical studies and/or clinical trials.

药物/毒性评估或与毒理学有关的问题进行咨询,以确认杂质已经得到充分评估,杂质在非临床研究和/或临床试验中被认为是合理的。

2.1.2       Immunogenicity, clinical, and clinical pharmacology assessments or consults, as appropriate, for immunological or other clinical concerns to assess the risk/benefit topatients.

免疫原性,临床和临床药理评估或咨询,免疫或其他临床问题,以评估患者的风险/收益。

2.2   In addition, the followingshould be considered in the assessment:

另外,评估时应考虑以下几点:

2.2.1       The proposed acceptance criterion may be supported by the data demonstrating that the impurity is asignificant metabolite. Whether a metabolite is clinically significant shouldbe the subject of pharm/tox and/or clinical pharmacology consults.

提出的接受标准可能可以通过证明杂质是重要代谢物的数据来支持。代谢产物是否具有重要临床意义应该是药物/毒理学和/或临床药理学研究的主题。

2.2.2       The proposed acceptance criterion for an ANDA or a 505(b)(2) NDA product may be supported by aside-by-side comparative impurity analysis for the proposed product and thelisted drug or RLD using the same analytical method that is shown to besuitable for its intended purpose. The comparative analysis is preferably to beconducted on multiple batches of the proposed product and the RLD. To support proposed new impurities or higher impurity levels than that of the RLD, theapplicant should submit a justification including a risk assessment (seesection 3.2 below on risk assessment).

对于ANDA或505(b)(2)NDA产品的拟定的标准可能通过产品与上市药物或参比制剂使用相同的分析方法进行并行比较杂质分析来支持其预期的目的。最好选用多批次产品和参比制剂进行比较分析。为了支持提出的新杂质或比参比制剂更高的杂质水平,申请人应提交包括风险评估的理由(参见下面的3.2部分风险评估)。

2.2.3       For those products that have USP monographs12 or other compendial monographs13and the monograph acceptance criteria are greater than the ICH Q3A(R2) orQ3B(R2) qualification thresholds, the monograph limits may be used only if thelimit is justified in an FDA-approved product.

对于那些有USP专论的产品[12]或其他药典专着[13],并且专论中的接受标准大于ICHQ3A(R2)或Q3B(R2)的接受标准,只有在FDA批准的产品中有合理说明的情况下,才可以使用专论标准。

3. BLAs and NDAs/ANDAs Excluded from ICH Q3A(R2) and Q3B(R2)

ICH Q3A(R2)和Q3B(R2)中排除的BLAs和NDAs / ANDAs

3.1    For those chemical drug substances and drug products (a) where monographs apply or (b) that are ANDA and 505(b)(2) NDA products (e.g.,peptides and fermentation products) and are not transitioning to BLA under the Biologics Price Competition and Innovation Act of 2009, recommendation soutlined in the above sections 2.1 and 2.2 should be followed.

对于那些化学原料药和制剂(a)适用专论的或(b)ANDA和505(b)(2)NDA的产品(例如多肽和发酵产品),并且在生物制品价格竞赛中不转换到BLA的化学药物和药品和“2009年创新法案”,应遵循上文第2.1和2.2节所述的建议。

3.2    For all other products, such as biologics, a determination of the acceptability of the proposed acceptance criteria of impurities supported by arisk assessment should be made by the product quality reviewer in consultation with other review disciplines including clinical, pharm/tox, immunogenicity, and clinical pharmacology, as appropriate. Assessments or consults should be initiated early during the review cycle to allow sufficient time for adequate review.

对于所有其他产品,例如生物制品,确定由风险评估支持的杂质的可接受标准的可接受性应由产品质量评审员酌情与临床,药物,毒性,免疫原性和临床药理学等其他评审学科协商制定。评估或咨询应在评审的早期进行,以便有足够的时间进行充分的评估。

3.2.1       A risk assessment will generally consider the impact of an impurity on activity, PK/PD, safety, and immunogenicity.

一个风险评估通常会考虑杂质对活性,PK/PD,安全性和免疫原性的影响。

3.2.2       A risk assessment can includeclinical data, nonclinical data (e.g., in vitro data and animal data), priorknowledge, and publicly available information.

一个风险评估可包括临床数据,非临床数据(例如体外数据和动物数据),优先知识和公开可获得的信息。

3.2.3       In some cases, uncertainty should be factored into the risk assessment. Uncertainty can be associated with the strength of the data to understand the clinical effect of an impurity aswell as analytical capability and analytics performance to identify and characterize the impurity. Principles laid out in the ICH Q914 and in an FDA scientificpublication15 describing how to manage the uncertainty with respect to the impact of product quality attributes on safety and/or efficacy may be followed.

在某些情况下,风险评估应考虑到不确定因素。不确定性可能与数据的强度有关,以了解杂质的临床效应以及分析能力和分析性能以鉴定和表征杂质。ICH Q9[14]中规定的原则和FDA的科学出版物[15]描述如何管理产品质量属性对安全性和/或功效的影响方面的不确定性。

3.2.4       For immunological concerns regarding products not reviewed by OBP, an immunogenicity consult may be requested from OBP to assess the immunogenicity risk of the impurities. The clinical reviewer on the review team will also evaluate the risk to patients.

对于未经OBP审查的产品的免疫学问题,可能要求OBP提供免疫原性咨询,以评估杂质的免疫原性风险。审评组的临床评审员也将评估患者的风险。

3.2.5       For toxicology-relatedconcerns, a pharm/tox assessment or consult should be made to verify that impurities have been adequately evaluated in nonclinical studies and/or clinical trials to assess the risk to patients for impurities at a specified level.

对于与毒理学相关的问题,应进行药物/毒物评估或咨询,以确认杂质是否在非临床研究和/或临床试验中得到充分评估,以评估患者在特定水平的杂质风险。
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